The goal of this research proposal is to study hematopoietic stem cell (HSC) transplantation and the development of tolerance to alloantigens in fetal and newborn mice. We will focus on H-2 mismatched and haplocompatible donor-recipient pairs which reflect possible human fetal transplants for marrow stem cell defects or inborn errors. If utero transplantation in the immunologically immature fetus could be accomplished, not only would toxic immunosuppression be avoided, but progressive organ damage in utero from at least some of these diseases might be prevented.
The specific aims are; 1) To quantitate the HSC in fetal liver and T depleted marrow and establish sustained engraftment in W(v)-anemic fetal recipients: 2) To assess the effect of in vivo T cell depletion and/or class I/II antigen expressing cell depletion in the recipient spleen and thymus on engraftment of allogeneic HSC: 3) To determine whether these in vivo interventions can be extended to the newborn mouse; 4) To assess the role of the recipient HSC marrow space in the engraftment of mismatched HSC and evaluate mechanisms for optimizing the relative number of donor erythroid progenitors which engraft; and 5) To study mechanisms of tolerance in engrafted animals. We will study matched, haplocompatible and H-2 mismatched HSC transplant systems (using either fetal liver or T depleted adult marrow/spleen as sources of HSC) in both normal and W(v)-anemic fetal and newborn recipient mice. We will study the effects of cell dose, in vivo selective immunosuppression and marrow stem cell depletion with monoclonal antibodies and preincubation with recombinant growth factors singly and in combination. The results of this study should provide a basis for developing curative approaches in utero for a variety of stem cell defects such as sickle cell anemia and thalassemia, and inborn errors such as the mucopolysaccharidoses.
